Methamphetamine (METH) abusers surviving emergency room treatment for METH overdose induced hyperthermia and seizures require treatment in the ensuing 1-2 weeks not only for the initial life-threatening symptoms but also for the prevention of the subsequent necrotic/apoptotic cascades which are not a current therapy. The strategy during the initial hyperthermia and seizures is not unlike those being formulated for hypoxia/excitoxicity due to such conditions as stroke. However the main question posed by this application is whether preventative and/or withdrawal treatment for METH toxicity and functional changes induced by METH binges could be developed. The other major treatment arm that is needed is for the treatment of the extended period of anergia (atypical depression) during withdrawal from chronic METH binges. Another aspect of long-term treatment relates to the hypothesized relationship between METH induced sensitization and the rapid escalation to high dose METH abuse, even after months of abstinence. Finally there should be an overriding concern that any treatment proposed for various conditions does not potentiate toxicity if METH is reintroduced. The goal of this project is to develop an animal model for chronic METH abuse, characterize the pathologies associated with this model and examine putative drug treatments for a realistic model of human METH abuse and withdrawal. We propose that a chronic METH dosing regimen will more closely approximate the human condition and that residual neurochemical and behavioral changes may be substantially different from those described for the frequently used acute one-day METH overdose model. Furthermore we plan to more fully characterize both models by using 1) state of the art electrochemical techniques such as Fast Cyclic Voltammetry (FCV) which can differentiate between dopamine (DA) release and uptake, and FCV coupled with photo-released caged DA methodology and 2) histological, HPLC and electrophoresis (Western Blot) methods to characterize the neuropathological and functional changes. We also plan to more extensively follow the residual behavioral states after METH treatment. Finally we will attempt to prevent and/or reverse the METH induced functional changes and neuropathologies using a spectrum of drugs chosen with respect to the results of our characterization of the chronic model.